Diuretic anils



United States Patent Office m 232, 1 62 The process using a beta-keto-aldehyde, or acetal there- 3,188,329 of, can be represented as follows: DIURETIC ANILS Jerry E. Robertson, Milwaukee, Wis., assignor to Colgate- V O Palmolive Company, a corporation of Delaware E C 'J No Drawing. Filed Apr. 10, 1962, Ser. No. 186,355

12 Claims. Cl. 260397.7) R

This invention relates to aniline derivatives. More par- R60 0 ticularly, this invention is concerned with novel anils, g 1 4 C-(IJH -R4,

processes of preparing the same and uses for such compounds. R 0 R,

According to the present invention there are provided 1 novel Z-Substituted sulfamyl-4-sulfamyl-N-(3-hydroxy-2- propenylidene)-anilines of the formula o Ig \CR4 /1 1'\ /i )Rs R X OH R: V y r NSO ,SO2N wherein R, R R R R R R and X haveithe assigned significance.

Representative of the aldehyde reactants that can be used in the processzare malonaldehyde, malonaldehyde tetraethylacetal, acetylacetaldehyde, acetylacetaldehyde dimethylacetal, '3-phenyl-3-oxopropanal, 3-benzyl-3-oxopropanal, 3-phenethyl-3-oxopropana1, propionylacetaldehyde, Z-methyl-S-phenyl-3-oxopropanal, 2 -phenylmalonaldehyde, 2 formylcyclohexanone, 2 for-my lcyclopentain which X is ahalogen such as chlorine and bromine, nitro or a halo-lower alkyl group such as chloromethyl and trifluoromethyl, R, R and R are the same or different groups such as hydrogen, lower alkyls such as methyl, ethyl, propyl and isopropyl, lower alkenyls such as allyl, lower alkynyl such as propargyl, aralkyl groups and particularly phenyl-lower alkyl groups such as benzyl, phenethyl and phenylisopropyl, and halo-lower alkyl groups such as 5,5,[i-trifluoroethyl, R is a group such as represented by R but is not hydrogen, R and R represent groups such as hydrogen, lower alkyls such as methyl, ethyl and propyl, aryl groups and particularly phenyl,

salts thereof such as the sodium and potassium salts which are converted in situ. to the free aldehydes. Many. of 5 these reactants, as Well as many others that can be. used are disclosed in Organic Reactions, John Wiley & Sons,

none, 2-formylcycloheptanone, acetals thereof with lower alcohols such as methanol and ethanohand alkali metal 1 aralkyl groups such as phenyl-lower alkyl groups includ- Inc. London, v01. VH1 1954 pages 164466. These I ing benzyl and phenethyl, and groups in which R; and R are joined to each other and constitute an alkylene having 3 to 5 carbons thereby forming cyclopentenyl, cyclohexenyl and cycloheptenyl rings.

The novel 2-R sulfamyl-4-sulfamyl-5-X-N-(3-hydroxyz'methylslllfamyl-4-S111famY1-5-(Moro-aniline, 2-propenylidene)-anilines of this invention are produced 2'dimethylslllfiamyb4-dimethylsulfamyl-5flfifillflroby reacting malonaldehyde or a beta-keto aldehyde, or methyl-311111116, acetals of such compounds formed from lower alcohols, 2-ethylslllfamyl-4-ethylsulfamyl-S-bI'OmO-aHiIiHe, with a 2-R sulfamyl-4-sulfamyl-5-X-aniline. This proc-- y a y y u my ess using the dialdehyde, or acetal thereof, can be repre- Y y y y fl m y sented as f llows; 2-dibenzylsulfamyl-4-dibenzylsulfamyl-5-nitro aniline,

o 0 2-allylsulfamyl-4-sulfamyl-S-chloro-aniline, 2-allysulfamy1-4-sulfarnyl-S-trifluoromethyhaniline, 2-allylsulfarnyl-4-sulfamyl-5-bromoaniline, X NHi RE I V jf 2-propargylsulfamyl-4-sulfiamyl-S-chlormahiline, 7 R R, or 2-benzylsulfamyl-4-sulfamyl-S-trifluoroacetylaminoso v aniline,

2-benzylsulfamyl-4-sulfamyl-5-chloro-aniline, R1 R3 OH-OH-Gfi 2-(beta-phenethyl)-sulfamyl-4-sulfamyl-S-trifluoro- R5 methyl-aniline, Y a

a 0 2-phenylisopropylsulfamyl-4-sulfamyl-5rchloro aniline,

2-propargylsulfamyl-4-sulfamylS-trifluoromethylaniline, p t N 3-1 2-(para-methoxybenzyl)sulfamyl-4-sulfamyl-5trifluoroa methyl-aniline, p,

R R2 2-benzylsulfamyl-4-sulfamyl-S-trifluoromethyI-aniline, 0 S 2- (beta-phenethyl) -sulfamyl-4-sulfamyl-5-chloro-aniline,

2-butenylsulfamyle4-sulfamyl-5-brom0 aniline, 31 R3 2-pentenylsulfamyl-4-sulfamyl 5-chloro-aniline, wherein R, R R R R and X have the assigned sig- Z-methylsulfamyl-5-nitro-4-sulfamylaniline, nificance and R is a lower alkyl such as methyl and ethyl. 2-ethylsulfamyl-5-nitro-4-sulfamylaniline,

reactants can also be used as alkali metal salts.

Some ofthe 2-R sulfamyl-4-sulfamyl-S-X-anilines 40 which can be used in the process are:

3 2-propylsulfamyl-5-nitro-4-sulfamylaniline, 2-allylsulfamyl-S-nitro-4-sulfamylaniline, 2-(5,5,B-trifiuoroethylsulfamyl)-5-nitro-4-sulfamylaniline, 2-phenylsulfamyl-5-nitro-4-sulfamylaniline, Z-benzylsulfamyl--nitro-4-sulfamylaniline, and 2- (beta-phenethyl )-sulfamyl-5intro-4 sulfamylaniline.

\ .Reaction between the aldehyde and the 2-R sulfamyl- 4-sulfamyl-5-X-anilines is effected by bringing the reactants together in a suitable solvent such as an alcohol including methanol and ethanol, dimethylformamide or an excess of the reacting aldehyde or acetal thereof. Water can be present in the reaction mixture. An acid catalyst such as aqueous hydrochloric acid is included in the mixture to promote the reaction. Temperatures from about room temperature to about 100 C. can be used satisfactorily. The reaction is generally completed in from about one hour to one day with a few hours being an approximate average reaction time. After the reaction is terminated, the solvent is removed as by evaporation under reduced pressure, the residue taken up in alcohol and crystallized from aqueous alcohol.

Among the products which are produced as described are:

2-methylsulfamyl-4-sulfamyl-5-chloro-N- 3-hydroxy- 2-butenylidene -aniline, 2-allylsulfamyl-4-sulfamyl-S-chloro-N-(3-hydroxy- 2-butenylidene)'-aniline, 2,4-bis-(dimethylsulfamyl)-5-chloro-N-(3-hydroxy- 2 butenylidene)-aniline, Z-methylsulfamyl-4-sulfamyl-S-trifluoromethyl-N-(3- hydroxyQ-butenylidene)-aniline, V '2-allylsulfamyl-4-sulfamyl-S-chloro-N- 3-hydroxy- 3-phenyl-2 propenylidene)-aniline, 2,4-bis (methylsulfamyl) -5-chloro-N- (3-hydroxy-2- butenylidene)-aniline, 2-methylsulfamyl-4-sulfamyl-S-trifiuoromethyl-N- 2- hydroxy-cyclohexen-1-ylmethylidene)-aniline and 2-ethylsu1famyl-4-sulfamyl-S-chloro-N- (3 -hydroxy- 2-butenylidene)-aniline as well as compounds of Table 1 following. I

Compound EX-481O is a particularly potent diuretic as shown by the test results in Table 2 following:

TABLE 2.-OOMPARISON OF DIURETIC EFFECT AFTER ORAL ADMINISTRATION OF EX-4810 AND HYDROCHLO- ROTHIAZIDE TO THE SAME GROUP OF DOGS Urin- Total 111. eq. for Six HoursiSJE. Dose, ary I mgJkg. Volume Na 01 K EX4810 0.1 141 33. 79:1:4. 52 39. 77i6. O1 8. 215:1. 53 Hydroehlorothiazide- 0.1 101 16.88512. 24 17. 365:1. 78 6. 455:1. 61

1 Average 0.5 hour percent increase for 6 hours.

The anil compounds of this invention can be administered in pharmaceutical unit-dosage forms formed by combining one or more of the active compounds with a pharmaceutical carrier such as talc or sucrose and then manufacturing capsules, tablets and powders therefrom using other additives as warranted. Such unit-dosage forms can contain about 5 to 500 mg., and advisably 5 to 100 mg., of one or more of the active compounds of this invention.

The compounds containing fully substituted sulfamyl groups are neutral and the compounds having partially substituted sulfamyl groups are weakly acidic.

The Z-substituted-4-sulfamyl-S-X-anilines, where X has the assigned meaning, used as starting materials are either disclosed in the art, orare producible by methods already published, or can be produced as hereinafter described. Some ofthe publications which disclose various starting materials are I. Am. Chem. 82, l1'32-1135 and 1161- 1166 (1960); J. Org. Chem. 25, 970/981 (1960); J. Org. Chem. 26, 3423-3433 and 4315-4325 (1961).

The 2,4-bis(substituted suIfamyD-S-X-anilines can be readily produced by known methods by reacting a S-X- TABLE 1 11 (i-Rs N /C-R X OH R R;

NSOQ SO3N X R R1 Ra R3 R4 R5 Ethyl--- H Ethyl Fl H H. Benzy1 H Benzyl H Methyl.- H. MethyL.-- Methyl Methyl Methyl Ethyl.--" H Phenyl--- H Phenyl H Methyl--- H H Ethyl Fl Methyl-- H. H- H Allyl H Phenyl--- Methyl. H H Propargyl..- H Benzyl H. H. H- Benzyl H R4+R =propylene. 'Allyl H Allyl H R4+R;,=butylene.

These ,novel anils are potent diuretic, natriuretic and antihypertensive agents in animals, including humans. Hence, they are useful in the treatment of congestive heart failure, in .the relief of edema and ascites as well as in the treatment of high blood pressure. One of the compounds, 2 allyl sulfamyl-5-chloro-4-sulfamyl-N-(3-hydroxy-2- bute'nylidene)-aniline (EX-4810), is considerably more potent than hydrochlorothiazide with respect to urinary and sodium output without a comparable increase in potassium excretion. The lack of concomitant increase in potassium excretion with increased diuretic potency would confer optimum therapeutic activity and a minimum of side effects due to potassium spillage.

aniline disulfonyl chloride with a primary or secondary amine as follows:

in which X, R and R have the assigned meanings.

The reactants of the formula X NH.

O NSO SOgNHRg in which X and R have the assigned meaning, except that X is not nitro, can be produced by reacting a 3-keto-7- sulfamyl ZH-l,2,4-benzothiadiazine-1,1-dioxide with an alkylating, alkenylating, alkynylating or aralltylating agent to produce a Z-substituted-3-keto-7-su1famyl-1,2,4-benzothiadiazine-1,1-dioxide and treating said compound with a base to open the ring and form a 2-substituted-sulfamyl-4- wherein X and R have the assigned meanings except that Xis not nitro here. 7

The 3-kkato -7-sulfamyl-2H-1,2,4-benzothiadiazine-l,l-dioxides used in this process can be produced as in J. Am. Chem. Soc. 82, 2042 (1960), and J. Am. Chem. Soc. 82,

The described process can be efiected by procedures in the literature as in J. Am. Chem. Soc. 82, 1132 (1960). Some of the compounds that can be produced in the first step of thisprocess are 2-allyl-3-keto-o-trifiuoromethyl-7-sulfamyl-1,2,4-benzothiadiazine-l, 1-dioxide,

thiadiazine-1,1-dioxide, 2-phenethyl-3 -keto-6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide,

' 2-propargyl-3-keto-6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide,

: 2-cinnarnyl-3-keto-6-trifluoromethyl-7-sulfamyl-1,2,4!

benzothiadiazine-l,1-dioxide, 2-benzyl-3-keto-6-chloro-7-sulfamyl-1,2,4-benzo thiadiazine-1,1-dioxide, Z-(beta-phenethyl)-3-keto-6-bromo-7-sulfarnyl-1,2,4-

benzothiadiazine and 2-allyl-3-keto-6-chloro-7-sulfamyl-1,2,4-benzothiadiazine.

Opening of the ring can be achieved in an aqueous inorganic basic medium at a moderately elevated tempera ture employing conventional techniques. Some of the compounds produced in this way are:

2-a1lylsulfamyl-4-sulfamyl-5-trifluoromethylaniline, 2-ethylsnlfamyl-4-su1famyl-5-chloroaniline,

, 2-propargylsulfamyl-4-sulfamyl-5-chloroaniline,

2-allylsulfamyl-4-sulfamyl-5-chloroaniline,

2-benzylsulfamyl-4-sulfamyl-5-trifluoromethylaniline, 2- (beta-phenethyl) 4-sulfamyl-5 -chloroaniline and 2-(beta-phenethyl)-4-sulfamyl-S-trifluoromethylaniline.

The compounds of the formula N r- NH.

NHZSO S OzNH-Rs where R has the assigned meaning, can be prepared by reacting 5-nitroaniline-2,4-disulfonylchloride first with ammonia and then with a monosubstituted amine. This process can be represented as follows:

wherein R has the assigned meaning.

The first step of the process is readily efiected by bringing 5-nitroaniline-2,4-disulfonylchloride intocontact with ammonia, advisably in a suitable solvent and particularly ethanol. The ammonia can be suitably employed dissolved in the ethanol. The reaction proceeds readily at room temperature and can be considered complete in 0.5 to 1 hour. The monosubstituted amine can then be added as in ethanol solution, to the reaction mixture. This reaction also proceeds at room temperature but slightly elevated temperatures-serve to promote the reaction. The desired product can be recovered by diluting the reaction mixture with water and partially evaporating the solution to precipitate out the product.

Some of the monosubstituted amines which can be used in the process are methylamine, ethylamine, propylamine, isopropylamine, allylamine, benzylamine, phenethylamine, aniline, ,B,fi,fl-trifluoroethylamine, proparglyamine, dimethylaminoethylamine and cinnamylamine.

Some of the products obtained as described have been named previously. Y

The following examples are presented to illustrate the invention.

EXAMPLE 1 Z-allylsulfamyl-S-chloro-4-sulfamylaniline 6-chloro-3,4-dihydro-3-keto-7-sulfamyl 1,2,4 benzothiadiazine-Ll-dioxide (14.8 g., 0.0475 mole) was dissolved in 50 ml. of dimethylformamide and 2.1 g. of 56.3% NaI-I in oil (0.0475 mole) was added with stirring at room temperature. After 0.5 hour of additional stirring, 6.05 g. (0.0475 mole) of allyl bromide was added and the mixture held at 6070 C. 'for 3 hours. After cooling, the reaction mixture was poured into 1.5 liters of Water. Cooling overnight gave a solid which was collected, washed with water, dissolved in dilute NaOH and reprecipitated'with dilute acetic acid. The resultant solid was collected, washed with water and dried to afford 13.4 g. (81%) of 2-allyl-6-chloro-3,4-dihydro-3-keto-7- sulfamyl-l,2,4-benzoth.iadiazine-1,l-dioxide, M.P. 28'5- 289 C.

Analysis.--Calcd. for C10H1QC1N305S2: S, C1, 10.07. Found: S, 17.97;Cl, 10.25.

2-allyl-6-chloro-3,4-dihydro 3-keto-7-sulfamyl 1,2,4- benzothiadiazin-e-1,1-dioxide (26.0 g., 0.075 mole) dissolved in 300 ml. of 15% NaOH was held at -100 C. for 7 hours. Cooling and addition of excess hydrochloric acid gave a solid which was collected, washed with water and recrystallized from dilute ethanol to alford 11.1 g. (45%) of the product as a monohydrate, M.P. 76-78 'C.

Analysis.-Calcd. for C H ClN O S S, 18.70. Found: S, 18.71.

Extended drying at C. gave the product as an amorphous solid. e 1

. Analysis.-Calcd. for C H ClNO O S S. 1972; C1, 10.89. Found: S. 19.48; Cl, 10.98.

EXAMPLE 2 cous solution was filtered. Addition of 6 drops of 10:1 H O/concentrated HCl, and stirring for 20 hours gave a heavy suspension. Dilution with 150 ml. of ethanol, collection of the solid, washing twice with 40 ml. portions of ethanol, and drying gave 6.2 g. (78%) of product, M.P. 204206 C.

Analysis.Calcd. for C H CIN O S Cl, 9.00; N, 10.67; S, 16.27. Found: Cl, 9.05; N, 10.79; S, 16.32. MIIHX. 343m (632,900).

EXAMPLE 3 2-methylsulfamyl-4-sulfamyl-j-trifluorometlzylar'ziline 3 keto-6-triflnoromethyl-7-sulfarnyl-2H-1,2,4-benzothiadiazine-1,1-dioxide (52.8 g., 0.152 mole) was dissolved in 125 ml. of dimethyl formamide. I Sodium hydride (3.7 g.,0.152 mole) wasadded in portions with stirring and the resultant solution was warmed to 70 C. After 15 minutes-at this temperature, 21.7 g. (0.153 mole) of methyl iodide was added dropwise and the mixture held at about 70 C. for another hour. The reaction solution was cooled and poured into 3.8 liters of cold water. After standing and cooling overnight, the solids which separated were collected, washed with water and dried. This crude product wasrecrystallized from acetonitrile (Darco) to afford 42.5 g. (77.1%) of pure 2-rnethyl-3-keto-6-trifluoromethyl 7-sulfamyl-1,2,4-benzothiadiazine-1,l-diox ide, M.P. 291-293" C. (dec.).

Analysis.Calcd. for C H N O S F N, 11.70; S, 17.85. Found: N, 11.70; S, 17.71.

2-methyl-3-keto-6-trifluorornethyl 7 sulfamyl 1,2,4- benzothiadiazine-l,l-dioxide (31.4 g., 0.087 mole) and 400 ml. of 10% sodium hydroxide solution were heated and stirred for 3 hours at 40 43 C., overnight at 5053 C., and 6 hours at 128130 C. Acidification with excess hydrochloric acid and cooling gave a solid which was collected, washed with waterand dried. Purification was affected by dissolution in 250 ml. boiling ethanol, treatment with charcoal, filtration and dilution to 700 ml. with water. Cooling gave the purified product which was collected, washed with water and dried. The solid was ground under benzene, collected and redried to afford 19.7 g. (67.7%) of product, M.P. 177-180" C.

Analysis.Calcd. for C H N O S F N, 12.61; S, 19.24. Found: N, 12.74; S, 19.50.

EXAMPLE 4 2-pr0pylsulfamyl-5-nitra-4-sulfzzmylaniline To a stirred suspension of 8.5 g. (0.025 mole) of 5- nitroaniline-2,4-disulfonyl chloride in 50 ml. of ethanol at 20 C. was added 10 ml. of cold 5.07 N ethanolic ammonia (0.050 mole) over about one hour. After stirring at about 20 C. for an additional hour, 5.9 g. (0.10 mole) of n-propylamine was added in one portion. The resultant exothermic reaction was controlled with an ice water bath. After one hour of standing at room temperature, the reaction mixture was reduced in vacuo in about onehalf of the original volume and then poured into 300 ml. of water. After standing atroom temperature for two days, the solid which separated was collected by filtration, washed with water, dried and pulverized to afford 6.0 g. (71%) of product, M.P. 148-453 C. (dec.).

Analysis.Calcd. for C H N O S N, 16.57; S, 18.93. Found: N, 16.10; S, 18.6 1.

EXAMPLE 5 5-nitr0-4-sulfamyl-2 -(5,flfi trifluoroethylsulfamyl)- aniline To a stirred suspension of 8.5 g. (0.025 mole) of 5- nitroaniline-2,4=disulfonyl chloride in 50 ml. of ethanol at 20 C. was added 10 ml. of 5.07 N ethanolic ammonia diluted with 15 m1. of ethanol over about 1 hour. After stirring at C. for an additional hour, 13.5 g. (0.10 mole) of Bfifi-trifluoroethylamine hydrochloride was 3 added in one portion and stirring was continued another 20 minutes. Triethylamine (10 g., 0.10 mole) was added in one portion with cooling and the mixture was stirred another hour at 20 C. Reduction of the volume by onehalf in vacuo and dilution to about. 300 ml. with water gave, after standing 2 days at room temperature, a solid. This material was collected, washed with water, dried, triturated with ether, and redried to afford 3.0 g. (32%) of product, M.P. 19920l C.

AizaZysis.-Calcd. for C H N O F N, 16.93; S, 14.81. Found: N, 17.10; S, 14.87.

EXAMPLE 6 5 -chZ0r0-2 ,4 -bis dim'etlzylsul famyl -N (3-hydr0ay-2- butenylz'dene) aniline 5 chloro 2,4 bis(dirnethylsulfamyl)aniline (2.0 g., 0.00585 mole), 3 ml. of acetylacetaldehyde dimethylacetal, and 3 drops of concentrated I-ICl were dissolved in 20 ml. of dimethylforrnamide and the solution was held at -100 C. for one hour. The solvent was removed in vacuo and the residue was dissolved in 60 ml. of ethanol. After a charcoal treatment, 1 liter of 3:2 n-hexaue-ether was added to the solution followed by cooling. A solid separated whichrwas collected and dried to afford 1.6 g. (89%) of product, M.P. 147149 C.

Analysis.Calcd. for C H ClN O S: Cl, 8.65, S, 15.64. Found: Cl, 8.76; S, 15.65. Amax. 345mg (635,660).

EXAMPLE 7 2-methylsulfamyl-4-sulfamyl-5-trifluoromethyl-N- (3- hydroxy-Z-butenylidene -aniline 2 methylsulfamyl-4-sulfamyl-5-trifluoromethylaniline (4.0 g., 0.012 mole), 8 ml. of acetylacetaldehyde dimethylacetal and 3 drops of 10:1 concentrated HCl-water were mixed with gentle warming to provide a solution. After standing at room temperature for 9 days, the amber solution was diluted with ml. of dry ether. A gum separated from which was decanted the solvent. The gum was dissolved in 50 ml. of ethanol, the resultant solution was filtered and 10 ml. of 10% aqueous NaOH was added. After a few minutes, the solution was diluted to 500 ml. with Water, adjusted to pH 6 with acetic acid and cooled. A solid separated which was collected, washed with water and dried to afiord 1.2 g. (25%) of product, M.P. 199- 200 C.

AIzalysis.-Calcd. for C12H14F3N305S2: C, H, 3.52; N, 10.47. Found: C, 36.45; H, 3.89; N, 10.33. )t max. 350 m, (6 30,600).

EXAMPLE 8 2-allylsulfamyl-5-chl0r0-4-sulfamyl-N- (3-hydr0xy- 3-pheny l-2-propenylidene) -aniline '2 allylsulfamyl-S-chloro-4-sulfamylaniline monohydrate (3.4 g., 0.01 mole) and 3.4 g. (0.02 mole) of the sodium salt of 3-phenyl-3-oxopropanal were slurried together in 50 ml. of ethanol and 5 ml. of concentrated HCl was added with stirring. After 3 minutes at room temperature, about 20 ml. of water was added. A yellow solid separated which was collected, washed with 2:1 ethanol-water, then other and dried to provide 2.1 g. (46%) of product, M.P. 232-233 C.

Analysis. Calcd. for C H ClN O S C, 47.50; H,.

3.98; CI, 7.78; S, 14.07. FoundzC, 47.45; H, 3.78; Cl, 7.83; S, 14.08. 7\ max. 372 my. (e 36,200).

EXAMPLE 9 5 -chl0r0-2,4 -bis(methylsulfamy l -N (3-hydr0xy-2- butenylidene)-aniline 5-ehloro-2,4-bis(methylsulfamyD-aniline (4.0 g., 0.013 mole) and 2 drops of concentrated HCl were dissolved in 25 ml. of acetylacetaldehyde dimethylacetal with 25 ml. of ethanol. After 3 hours at room temperature, the solu- EXAMPLE 10 2-methyl-sulfamyl-4-sulfamyl-5-trifluor0methyl-N- (Z-hydroxycyclohexen-I-yl methylidene)-aniline 2 methylsulfamyl-4-sulfamyl-5-trifluoromethylaniline (3.3 g., 0.010 mole) and 2.6 g. (0.020 mole) of freshly distilled 2-formylcyclohexauone were dissolved in 15 ml.

of ethanol and 3 drops. of concentrated HCl was added.

A solid formed after standing overnight. The mixture was diluted with ethanol and the solid was collected, washed with ethanol and dried to provide 2.5 g. (56%) of product, M.P. 214-216 C.

Analysis.Calcd. 01 C15H1BF3N305S2: N, S, 14.52. Found: N, 9.42; S, 14.40. A max. 368 ma (6 31,000).

EXAMPLE 11 Z-ethylsulfamyl-4-sulfamyl-5-chloro-N-(S-hydroxy- 2-butenylidene)-aniline 5 chloro-2-ethylsulfamyl-4-sulfamylaniline (1.0 g., 0.0032 mole) and 2 drops of 10:1 water/concentrated HCl were dissolved in 5 ml. of acetylacetaldehyde dimethylacetal. After standing overnight at room temperature,

the resultant slurry was diluted with 10 ml. of ethanol.

The solid was collected, washed with ethanol and dried to provide 1.0 g. (81%) of product, M.P. 235-236 C.

Analysis.Calcd. for C H ClN O S C, 37.73; H, 4.23. Found: C, 37.98; H, 4.17. A max. 343 mu. (6 35,750).

EXAMPLE 12 EXAMPLE l3 5 -nitr-2-pr0pylsulfamyl-4-sulfamyl-N (3-hydr0xy- Z-butenylidene) -aniline A solution of 7 drops 10:1 water/concentrated HCl and 1.0 g. (0.003 mole) of 2-propylsulfamyl-5-nitrio-4- sulfamyl-aniline in ml. of acetylacetaldehyde dimethylacetal was allowed to stand at room temperature for 20 hours. Dilution with ml. of ethanol, then 100 ml. of water and cooling gave a solid which was collected, washed with water and dried to afford 0.8 g. (64%) of product, M.P. 188190 C. A max. 334 m (e 26,200).

EXAMPLE 14 Z-m'ethylsulfamyl-5-nitr04-sulfamylaniline To a stirred slurry of 6.7 g. (0.020 mole) of 4-amino- 6-nitro-l,3-benzenedisulfonyl chloride in 50 ml. of absolute ethanol was added 15.0 ml. of a 2.81 N solution of ammonia (0.040 mole) in absolute ethanol over one hour at about C. After stirring for an additional hour at 20 C., 20 ml. of 3.7 N methylamine in absolute ethanol was added in one portion and after stirring for one more hour the mixture was reduced under vaccum to about 40 ml, diluted with 300 ml. of water, treated with activated charcoal, filtered and the filtrate stripped to a gum. This residue was crystallized twice from dilute ethanol to afiord 2.0 g. (32%) of products, M.P. 205-206 C.

Analysis.-Calcd. for CqH10N4O S2Z S, 20.72. Found: S, 20.72. i

EXAMPLE 15 Z-ethylsulfamyl-5-nitr0-4-sulfumy[aniline This product is produced by a procedure identical to that given in Example 14 except that ethylamine is used in place of methylamine;.M.P. 16817 l C.

, EXAMPLE 16 x Z-benzylsulfamyl-4-sulfamyI-S-trifluoromethyl-aniline To a solution of 20.7 g. (0.060 mole) of 3,4-dihydro- 3 keto 7-sulfamyl-6-trifluoromethyl-1,2,4-benzothiadiazine-1,l-dioxide in 40 ml. of dimethylformamide was added 2.6 g. of 53% sodium hydride oil (0.060 mole). An exothermic reaction ensued. After stirring at room temperature for one hour, 10.4 g. (0.061 mole) of benzyl bromide was added dropwise. After stirring at room temperature for an additional hour, the reaction mixture was held at 60 C. for one hour. Cooling and dilution with 1.2 liters of water induced an oil to separate which crystallized on standing. This solid was collected,

washed with heptane, and dried to afiord 10 g. of crude product, M.P. 210- 213 C. The crude product was triturated with chloroform and further purified by dissolution in dilute sodium hydroxide and reprecipitated with dilute acetic acid to afford 7.8 g. (30%) of pure 2-benzyl-3, 4 dihydro 3-keto-7sulfamyl-6-trifluoromethyl-1,2,4- benzothiadiazine-l,l-dioxide, M.P. 22923l C.

Analysis.-Calcd. for C15H12N3O5S2F3: N, S, 14.73. Found: N, 9.68; S, 14.49.

A solution of 7.8 g. (0.018 mole) of 2-benzyl-3,4-dihydro 3 keto-7-sulfamyl-6-trifluoromethyl-1,2,4-benzothiadiazine-1,1-dioxide in 70 ml. of 10% sodium hydroxide was refluxed and stirred for 6 hours. Cooling, adjustment of the pH to 2-3 with concentrated hydrochloric acid and further cooling afforded a solid which was collected, washed with water and dried. Recrystallization of this crude product from ethanol (charcoal) gave 4.6 g. (63.1%) of pure product, M.P. l194 C.

Analysis-Calcd. for C H N O S F N, 10.26; S, 15.66. Found: N, 10.19; S, 15.46.

Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of this invention, they are intended to be included within the scope of the appended claims.

What is claimed is:

1. Compound of the formula wherein X is a member of the group consisting of halogen, nitro and halo-lower alkyl, R, R and R are members of the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl and halo-lower alkyl R is a member of the group consisting of lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl and halo-lower alkyl, and R and R represent members of the group consisting of hydrogen, lower alkyl, phenyl, phenyl-lower alkyl and groups in which R and R are joined to each other and together constitute a lower alkylene having 3 to 5 carbons. A

2. 2-lower alkyl sulfamyl-4-sulfarnyl'5-halo-N-(3-hydroxy-Z-butenylidene)-ani1ine.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,188,329 June 8, 1965 Jerry E. Robertson It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 4, line 39, for "970/981" read 970-981 same column 4, lines 71 to 75, fortheright han'd' portion of the formula reading read N :olumn 5, lines 3 to 6, for the lower left-hand portion of the ormula reading O NSO read H NSO olumn 6, line 67, for "N0 read N same line 67, for 1972" read 19.72 column 9, line 75, for "vaccum" read vacuum column 10, line 4, for "products" read roduct Signed and sealed this 23rd day of November 1965.

SEAL) ttest:

RNEST W. SWIDER EDWARD J. BRENNER ttesting Officer Commissioner of Patents 

1. COMPOUND OF THE FORMULA 